Tiotropium is an anticholinergic agent and is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Tiotropium is marketed as Spiriva® in the form of an inhalation powder or solution for inhalation.
The present invention is directed to a formulation of tiotropium. Tiotropium contains a quaternary ammonium cation and is typically used as the bromide salt which has the following structure:

The two most common approaches for formulating inhalable medicaments for use outside of the emergency room are the dry powder inhaler (DPI) and the pressurised metered dose inhaler (pMDI). An example of the DPI is the marketed inhalation powder. The inhalation powder contains tiotropium bromide monohydrate and lactose stored in a hard capsule and is administered using the HandiHaler® dry powder inhaler. However, the pMDI is an alternative approach to delivering tiotropium bromide to the lungs. Typically patient compliance is greater with a pMDI as they tend to be easier to use. Moreover, the DPI suffers from the drawback that only a small portion of the powdered active ingredient is actually inhaled into the lungs.
pMDI formulations may be presented as suspensions or solutions. WO 03/082252 provides an example of tiotropium bromide monohydrate in HFA 134a or 227 formulated as a suspension. In a solution formulation, the active ingredient is dissolved in the propellant system and hence avoids problems such as potential blockage of the pMDI dispensing nozzle orifice, physical instability of the suspended particles and the requirement to use suspending agents such as surfactants. Solution formulations are also easier to manufacture. However, a significant problem associated with formulating tiotropium salts as a solution formulation is that the active ingredient is chemically unstable in the presence of the co-solvents, such as ethanol, required to solubilise the active ingredient in the HFA propellant.
The marketed solution for inhalation circumvents this problem by avoiding the pMDI altogether. Instead, the product employs the Respimat® “soft-mist inhaler”. The formulation contains tiotropium bromide, benzalkonium chloride, disodium edentate, purified water and hydrochloric acid 3.6% (for pH adjustment). Instead of using a liquefied propellant, the Respimat® inhaler produces a mist by the action of a spring within the inhaler. However, the pMDI is a preferred approach and a number of attempts have been made to formulate tiotropium as a pMDI formulation.
WO 94/13262 discloses the use of inorganic or organic acids to stabilise solution formulations. However, the disclosure therein is principally directed to ipratropium bromide and it is not apparent how the approach should be modified to apply to tiotropium.
US 2005/0058606 addresses the problem of stabilising a tiotropium bromide solution formulation also using inorganic or organic acids.
However, significant concerns have arisen over the use of acids to stabilise solution formulations as the acids themselves can react with the metallic surface of the canister leading to the leaching of metal salts into the formulation which can lead to further instability of the active ingredient and/or contamination of the formulation. For example, EP 1 666 029 discloses pMDI solution formulations in which the internal surfaces of the inhaler consist of stainless steel or anodised aluminium, or in which the internal surfaces are lined with an inert organic coating, in order to minimise the effects of the canister on the chemical instability of the active ingredient. In addition, EP 2 201 934 describes a pMDI formulation containing a tiotropium salt, an HFA propellant, one or more co-solvents and a mineral acid. This document teaches the importance of using an aerosol can fitted with sealing rings and gaskets which are in contact with the formulation, made of a butyl or halo-butyl rubber, in order to avoid adverse interactions of the acid-containing formulation with the materials of the rings and gaskets.
There remains, therefore, a need in the art for pMDI solution formulations of tiotropium salts which are chemically stable and which do not adversely react with the internal surfaces of the inhaler.